Chronic autoimmune diseases affect millions of people worldwide and thus, have a tremendous social, economic and political impact. Type I diabetes (T1D) is one of the most common chronic diseases in children and adolescents; more than 13,000 young adults are diagnosed with T1D each year. T cells are considered a main player in the destruction of insulin-producing -cells during T1D development; however, the initiating factors contributing to T cell recruitment and islet inflammation and destruction are largely unknown. Innate immune defects involving activation of viral sensors and subsequent type I interferon (IFN-I) responses have been implicated in the pathogenesis of T1D. Plasmacytoid dendritic cells (pDC) have been identified as a major source of IFN-I in diabetic mouse models and an expansion of IFN-I-producing pDC has been observed in human patients with T1D around the time of diagnosis. pDC are antigen presenting cells that specialize in the secretion of IFN-I in response to both viral and endogenous DNA/RNA. Thus, elimination of pDC or blocking their IFN-I production may prevent immunopathology in T1D. On the other hand, in models of virus-induced T1D, pDC and IFN-I may reduce viral burden and trigger tolerogenic mechanisms that are protective. Based on these observations and our preliminary results, the long-term goal of this study is to understand the link between pDC, IFN-I and T1D development. Whether pDC do, in fact, promote or protect against T1D, can be firmly established by specifically depleting these cells in diabetic mouse models. The rationale behind our approach is that understanding the nature and function of the cell types involved in mediating detrimental or beneficial immune responses can lead to better treatment and therapeutic strategies for chronic autoimmune diseases such as T1D, that might ease financial burden and improve quality of life. We propose two specific aims: Specific Aim 1. To determine the impact of pDC on autoimmune diabetes Specific Aim 2. To determine the impact of pDC on virus-induced diabetes These aims will provide insights into roles of pDC during autoimmune and virus-induced T1D. We are confident that addressing these specific aims using our cutting edge approach for inducing pDC depletion and expertise in pDC biology will yield invaluable information regarding the potential of pDC- depleting antibodies or pDC-activating drugs for therapeutic intervention in T1D.